This proposal is an extention of a career development award (5K99-DA025182-02) for Dr. Michael R. Bruchas, who is trained as a pharmacologist, and has focused his research career studying the molecular, cellular, and behavioral components of stress and addiction. The proposed project, is to be conducted at Washington University-St. Louis, in the Departments of Anesthesiology & Anatomy/Neurobiology, a strong and enriching environment for neuroscience research. The proposal's overall goal is to better understand the neuronal relationship between stress and drug seeking. Specifically, it concerns Kappa opioid receptor (KOR) signaling and noradrenergic mechanims in stress and drug seeking. Recently, Kappa opioid receptors were shown to regulate stress-induced behavioral responses to drugs of abuse, including stress-induced reinstatement (termed relapse in humans), and potentiation of cocaine-conditioned place preference. We and others have also demonstrated that kappa opioid receptors couple to mitogen-activated protein kinase (MAPK) signaling cascade, that is required for these behaviors. In addition, it has been suggested that KOR systems interact with noradrenergic systems, although the behavioral consequences, molecular and cellular nature of these interactions are poorly understood. This proposal has 2 specific aims: 1) To determine the anatomical brain regions, subpopulations, and cell types where kappa opioid and noradrenergic circuits converge following behavioral (stress) and pharmacological stimuli. 2) To determine how stress and dynorphin/KOR activation regulate noradrenergic circuits to ultimately influence cocaine and methamphetamine reward. We will investigate noradrenergic systems, the mediation of KOR-dependent behavioral responses, and interaction between both systems. This project will investigate the anatomical relationships (receptors, cell types, regions) where opioid and noradrenergic circuits converge, and their respective roles in drug-seeking behavior. This project's goal is to further define the pharmacological and physiological mechanisms of stress-induced drug reward by dissecting the dynorphinergic and noradrenergic brain circuitry involved in the interactions between stress and drugs of abuse.